Clinical outcomes and prognostic factors to predict treatment response in high risk neuroblastoma patients receiving topotecan and cyclophosphamide containing induction regimen: a prospective multicenter study

Piya Rujkijyanont, Apichat Photia, Chanchai Traivaree, Chalinee Monsereenusorn, Usanarat Anurathapan, Panya Seksarn, Darintr Sosothikul, Piti Techavichit, Kleebsabai Sanpakit, Kamon Phuakpet, Surapon Wiangnon, Thirachit Chotsampancharoen, Su-On Chainansamit, Somjai Kanjanapongkul, Arunotai Meekaewkunchorn, Suradej Hongeng, Piya Rujkijyanont, Apichat Photia, Chanchai Traivaree, Chalinee Monsereenusorn, Usanarat Anurathapan, Panya Seksarn, Darintr Sosothikul, Piti Techavichit, Kleebsabai Sanpakit, Kamon Phuakpet, Surapon Wiangnon, Thirachit Chotsampancharoen, Su-On Chainansamit, Somjai Kanjanapongkul, Arunotai Meekaewkunchorn, Suradej Hongeng

Abstract

Background: Neuroblastoma is the most common extra-cranial solid tumor among children. Despite intensive treatment, patients with advanced disease mostly experience dismal outcomes. Here, we proposed the use of topotecan and cyclophosphamide containing induction regimen as an upfront therapy to high risk neuroblastoma patients.

Methods: Patients with high risk neuroblastoma undergoing ThaiPOG high risk neuroblastoma protocol from 2016 to 2017 were studied. All patients received 6 cycles of induction regimen consisting of 2 cycles topotecan (1.2 mg/m2/day) and cyclophosphamide (400 mg/m2/day) for 5 days followed by cisplatin (50 mg/m2/day) for 4 days combined with etoposide (200 mg/m2/day) for 3 days on the third and fifth cycles and cyclophosphamide (2100 mg/m2/day) for 2 days combined with doxorubicin (25 mg/m2/day) and vincristine (0.67 mg/m2/day) for 3 days on the fourth and sixth cycles. Treatment response after the 5th cycle before surgery and treatment-related toxicities after each topotecan containing induction cycle were evaluated. Relevant prognostic factors were analyzed to measure the treatment response among those patients.

Results: In all, 107 high risk neuroblastoma patients were enrolled in the study. After the 5th cycle of induction regimen, the patients achieved complete response (N = 2), very good partial response (N = 40), partial response (N = 46) and mixed response (N = 19). None of the patients experienced stable disease or disease progression. The most significant prognostic factor was type of healthcare system. The most common adverse effect was febrile neutropenia followed by mucositis, diarrhea and elevated renal function.

Conclusion: The topotecan and cyclophosphamide containing induction regimen effectively provides favorable treatment response. The regimen is well tolerated with minimal toxicity among patients with high risk neuroblastoma in Thailand.

Keywords: High risked neuroblastoma; Induction therapy; Prognostic factor; Topotecan; Treatment response; Treatment-related toxicity.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Induction response based on health care systems (university- versus community-based health care system). Notes:Graphs are shown as number (%). Abbreviations:CR, complete response; VGPR, very good partial response; PR, partial response; MR, mixed response
Fig. 2
Fig. 2
Treatment-related toxicities according to health care systems (university- versus community-based health care system) after first cycle (a) and second cycle (b) of topotecan and cyclophosphamide containing induction therapy . Notes:Graphs are presented as number (%). p-value was obtained from Fisher’s exact test, and p < 0.05 is statistically significant (*)

References

    1. Maris JM, Hogarty MD, Bagatell R, Cohn SL. Neuroblastoma Lancet. 2007;369(9579):2106–2120. doi: 10.1016/S0140-6736(07)60983-0.
    1. Perel Y, Valteau-Couanet D, Michon J, Lavrand F, Coze C, Bergeron C, et al. Prognosis of neuroblastoma in childhood. Methods of assessment and clinical use. Arch Pediatr. 2004;11(7):834–842. doi: 10.1016/j.arcped.2004.02.022.
    1. Louis CU, Shohet JM. Neuroblastoma: molecular pathogenesis and therapy. Annu Rev Med. 2015;66:49–63. doi: 10.1146/annurev-med-011514-023121.
    1. Cohn SL, Pearson AD, London WB, Monclair T, Ambros PF, Brodeur GM, et al. The international neuroblastoma risk group (INRG) classification system: an INRG task force report. J Clin Oncol. 2009;27(2):289–297. doi: 10.1200/JCO.2008.16.6785.
    1. Pinto NR, Applebaum MA, Volchenboum SL, Matthay KK, London WB, Ambros PF, et al. Advances in risk classification and treatment strategies for neuroblastoma. J Clin Oncol. 2015;33(27):3008. doi: 10.1200/JCO.2014.59.4648.
    1. Maris JM. Recent advances in neuroblastoma. N Engl J Med. 2010;362(23):2202–2211. doi: 10.1056/NEJMra0804577.
    1. Ladenstein R, Pötschger U, Pearson AD, Brock P, Luksch R, Castel V, et al. Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial. Lancet Oncol. 2017;18(4):500–514. doi: 10.1016/S1470-2045(17)30070-0.
    1. Zage PE. Novel Therapies for Relapsed and Refractory Neuroblastoma. Children(Basel). 2018;5(11).
    1. Smith V, Foster J. High-Risk Neuroblastoma Treatment Review. Children (Basel). 2018;5(9).
    1. MacFarland S, Bagatell R. Advances in neuroblastoma therapy. Curr Opin Pediatr. 2019;31(1):14–20. doi: 10.1097/MOP.0000000000000711.
    1. Matthay KK, Reynolds CP, Seeger RC, Shimada H, Adkins ES, Haas-Kogan D, et al. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children's oncology group study. J Clin Oncol. 2009;27(7):1007–1013. doi: 10.1200/JCO.2007.13.8925.
    1. Stewart DJ. Topotecan in the first-line treatment of small cell lung cancer. Oncologist. 2004;9(Suppl 6):33–42. doi: 10.1634/theoncologist.9-90006-33.
    1. Stewart DJ. Update on the role of topotecan in the treatment of non-small cell lung cancer. Oncologist. 2004;9(Suppl 6):43–52. doi: 10.1634/theoncologist.9-90006-43.
    1. Ardizzoni A. Topotecan in the treatment of recurrent small cell lung cancer: an update. Oncologist. 2004;9(Suppl 6):4–13. doi: 10.1634/theoncologist.9-90006-4.
    1. Saylors RL, 3rd, Stine KC, Sullivan J, Kepner JL, Wall DA, Bernstein ML, et al. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric oncology group phase II study. J Clin Oncol. 2001;19(15):3463–3469. doi: 10.1200/JCO.2001.19.15.3463.
    1. Saylors RL, 3rd, Stewart CF, Zamboni WC, Wall DA, Bell B, Stine KC, et al. Phase I study of topotecan in combination with cyclophosphamide in pediatric patients with malignant solid tumors: a Pediatric oncology group study. J Clin Oncol. 1998;16(3):945–952. doi: 10.1200/JCO.1998.16.3.945.
    1. Simon T, Langler A, Berthold F, Klingebiel T, Hero B. Topotecan and etoposide in the treatment of relapsed high-risk neuroblastoma: results of a phase 2 trial. J Pediatr Hematol Oncol. 2007;29(2):101–106. doi: 10.1097/MPH.0b013e3180320b48.
    1. Feng C, Tang S, Wang J, Liu Y, Yang G. Topotecan plus cyclophosphamide as maintenance chemotherapy for children with high-risk neuroblastoma in complete remission: short-term curative effects and toxicity. Nan Fang Yi Ke Da Xue Xue Bao. 2013;33(8):1107–1110.
    1. Ashraf K, Shaikh F, Gibson P, Baruchel S, Irwin MS. Treatment with topotecan plus cyclophosphamide in children with first relapse of neuroblastoma. Pediatr Blood Cancer. 2013;60(10):1636–1641. doi: 10.1002/pbc.24587.
    1. London WB, Frantz CN, Campbell LA, Seeger RC, Brumback BA, Cohn SL, et al. Phase II randomized comparison of topotecan plus cyclophosphamide versus topotecan alone in children with recurrent or refractory neuroblastoma: a Children's oncology group study. J Clin Oncol. 2010;28(24):3808–3815. doi: 10.1200/JCO.2009.27.5016.
    1. Park JR, Stewart CF, London WB, Santana VM, Shaw PJ, Cohn SL, et al. A topotecan-containing induction regimen for treatment of high risk neuroblastoma. J Clin Oncol. 2006;24(18_suppl):9013.
    1. Park JR, Scott JR, Stewart CF, London WB, Naranjo A, Santana VM, et al. Pilot induction regimen incorporating pharmacokinetically guided topotecan for treatment of newly diagnosed high-risk neuroblastoma: a Children's oncology group study. J Clin Oncol. 2011;29(33):4351–4357. doi: 10.1200/JCO.2010.34.3293.
    1. De Ioris MA, Castellano A, Ilari I, Garganese MC, Natali G, Inserra A, et al. Short topotecan-based induction regimen in newly diagnosed high-risk neuroblastoma. Eur J Cancer. 2011;47(4):572–578. doi: 10.1016/j.ejca.2010.10.023.
    1. Park JR, Kreissman SG, London WB, Naranjo A, Cohn SL, Hogarty MD, et al. A phase III randomized clinical trial (RCT) of tandem myeloablative autologous stem cell transplant (ASCT) using peripheral blood stem cell (PBSC) as consolidation therapy for high-risk neuroblastoma (HR-NB): A Children's Oncology Group (COG) study. J Clin Oncol. 2016;34(18_suppl):LBA3–LLBA. doi: 10.1200/JCO.2016.34.18_suppl.LBA3.
    1. Park JR, Eggert A, Caron H. Neuroblastoma: biology, prognosis, and treatment. Pediatr Clin N Am. 2008;55(1):97–120. doi: 10.1016/j.pcl.2007.10.014.
    1. Whittle SB, Smith V, Doherty E, Zhao S, McCarty S, Zage PE. Overview and recent advances in the treatment of neuroblastoma. Expert Rev Anticancer Ther. 2017;17(4):369–386. doi: 10.1080/14737140.2017.1285230.
    1. Bhatnagar SN, Sarin YK. Neuroblastoma: a review of management and outcome. Indian J Pediatr. 2012;79(6):787–792. doi: 10.1007/s12098-012-0748-2.
    1. Bansal D, Totadri S, Chinnaswamy G, Agarwala S, Vora T, Arora B, et al. Management of neuroblastoma: ICMR consensus document. Indian J Pediatr. 2017;84(6):446–455. doi: 10.1007/s12098-017-2298-0.
    1. Park JR, Bagatell R, Cohn SL, Pearson AD, Villablanca JG, Berthold F, et al. Revisions to the international neuroblastoma response criteria: a consensus statement from the National Cancer Institute clinical trials planning meeting. J Clin Oncol. 2017;35(22):2580–2587. doi: 10.1200/JCO.2016.72.0177.
    1. Brodeur GM, Pritchard J, Berthold F, Carlsen NL, Castel V, Castelberry RP, et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993;11(8):1466–1477. doi: 10.1200/JCO.1993.11.8.1466.
    1. Gelormino E, Bambra C, Spadea T, Bellini S, Costa G. The effects of health care reforms on health inequalities: a review and analysis of the European evidence base. Int J Health Serv. 2011;41(2):209–230. doi: 10.2190/HS.41.2.b.
    1. Karanikolos M, Ellis L, Coleman MP, McKee M. Health systems performance and cancer outcomes. J Natl Cancer Inst Monogr. 2013;2013(46):7–12. doi: 10.1093/jncimonographs/lgt003.
    1. Scialdone L. Overview of supportive care in patients receiving chemotherapy: antiemetics, pain management, anemia, and neutropenia. J Pharm Pract. 2012;25(2):209–221. doi: 10.1177/0897190011431631.
    1. Steinberg ML. Inequity in cancer care: explanations and solutions for disparity. Semin Radiat Oncol. 2008;18(3):161–167. doi: 10.1016/j.semradonc.2008.01.003.
    1. Alvarez E, Keegan T, Johnston EE, Haile R, Sanders L, Saynina O, et al. Adolescent and young adult oncology patients: disparities in access to specialized cancer centers. Cancer. 2017;123(13):2516–2523. doi: 10.1002/cncr.30562.
    1. Wolfson J, Sun CL, Kang T, Wyatt L, D'Appuzzo M, Bhatia S. Impact of treatment site in adolescents and young adults with central nervous system tumors. J Natl Cancer Inst. 2014;106(8):dju166. doi: 10.1093/jnci/dju166.
    1. Wolfson J, Sun CL, Wyatt L, Stock W, Bhatia S. Adolescents and young adults with acute lymphoblastic Leukemia and acute myeloid Leukemia: impact of Care at Specialized Cancer Centers on survival outcome. Cancer Epidemiol Biomark Prev. 2017;26(3):312–320. doi: 10.1158/1055-9965.EPI-16-0722.
    1. Wolfson JA, Sun CL, Wyatt LP, Hurria A, Bhatia S. Impact of care at comprehensive cancer centers on outcome: results from a population-based study. Cancer. 2015;121(21):3885–3893. doi: 10.1002/cncr.29576.

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